Research Interest: 1. Development of new methods and biologically orthogonal chemical tools for chemical biology and drug discovery
We are specifically interested in applying chemical probes in epigenomics research and structure-, ligand-, and fragment-based drug design.

Epigenomics – photoreactive histone deacetylase probes and inhibitors: Histone deacetylases (HDACs) comprise a family of enzymes that regulate chromatin remodeling, gene transcription and activity of partner proteins. They control critical cellular processes, including cell growth, cell cycle regulation, DNA repair, differentiation, proliferation, and apoptosis. Chemical inhibitors of HDACs have been shown to inhibit tumor cell growth and induce differentiation and cell death. It is hypothesized that depending on HDAC isoform selectivity HDAC ligands can be either cytotoxic or neuroprotective. The development of isoform-selective HDAC inhibitors would be a significant step in reducing off-target effects of HDAC-based therapeutics.
One of the key challenges in designing isoform-selective HDAC inhibitors is a poor understanding of the binding modes (poses) available to the highly solvent exposed surface binding group (SBG) of HDAC inhibitors targeting the grooves and ridges on the protein surface directly adjacent to the catalytic well of HDACs. It has been hypothesized that the SBG groups may have more than one preferred position on the surface and each of them contributes to the overall binding affinity. Although the available HDAC X-ray data provide information on structure of proteins and binding of ligands, its use is limited due to high solvent exposure of the SBG of the ligands and additional copies of the same protein in the crystallographic cell that interfere with the binding of the co-crystallized ligands.

We focus our research on the design and use of photoreactive probes, liquid chromatography-tandem mass-spectrometry, and molecular dynamics simulations to map the ensemble of the poses of HDAC8 inhibitors upon binding or BEProFL – (B)inding (E)nsemble (Pro)filing with (F)photoaffinity (L)abeling. Our methodology supplies a unique power in analysis of the binding of ligands to their macromolecular targets by expanding the data typically obtained in the protein x-ray crystallography or providing an alternative tool when co-crystallization of the protein with the ligand of interest has failed. Most importantly, the binding poses are determined by BEProFL in solution and, thus, the captured “snapshots” reflect the dynamic nature of the ligand and its macromolecular target conformations. Extension of the BEProFL approach to study the binding poses of the ligands in cells is in progress in our laboratory. The approach has the potential not only to guide ligand optimization but also to become a new tool in disciplines such as molecular modeling, development, validation and application of computer-aided drug design methods, especially those for rapid prediction of the protein-ligand interactions such as docking and scoring.

2. Translation of the chemical biology approaches to medicinal chemistry and computer-aided drug design and their application for design of therapeutically relevant compounds

The current focus is on the development of the BEProFL probes and inhibitors for malate synthase, pantothenate synthetase, beta-secretases 1 and 2, and calpain.